Twenty years of research in the field of HIV vaccine have shown that the use of replicating virus to stimulate the immune system is one of our best hopes to develop a vaccine. Recently a cytomegalovirus based vaccine strategy has successfully protected half of the animals vaccinated. However, this success rate needs to be improved, notably by the use of live viral vectors that restrict HIV replication at the mucosal portal of entry. The capacity of humoral and cellular immune responses in mucosal tissues to block or contain replication at the initial stage of virus transmission may have a profound impact on the ability of a vaccinated host to resist infection. An ideal vaccine should provide a life-lon stimulation of the immune system with viral antigens and should focus the immune response at the site of primary replication of HIV. Recent breakthroughs in vaccine development have used highly immunogenic viruses like particles (VLP) as antigen carriers to stimulate the immune system. This is particularly true for Papillomaviruses (PV). These VLP can also be used to encapsidate either fully infectious PV genome or expression plasmids. These particles are infectious both in cell culture and in vivo. A PV called RhPV has been isolated from a Rhesus macaque giving the opportunity to test PV as SIV antigen vectors. Our collaborator has recently been using pseudotyped RhPV successfully to inoculate Rhesus macaques giving the possibility to manipulate this virus without losing infectivity. The use of RhPV as a SIV vaccine in macaque will be the best model possible to investigate the potential of HPV as an anti-HIV vaccine in human. Therefore, specific aims of the R21 will be: 1) To design and optimize a RhPV vector that leads to long-term expression of SIV antigens in rhesus macaques vaccinated by vaginal, route; and, 2) To experimentally infect female macaques with a chimeric RhPV/SIV and investigate the nature of the immune responses induced. Our work should provide a proof-of-concept for the development of HIV vaccines using the papillomavirus as a delivery system at the mucosa to elicit long-term protection against HIV infection.